The present invention relates to a process for the preparation of Iopamidol and ketals of 2-amino-1,3-propanediol. More particularly the invention relates to a process for the preparation of 5-amino-2,2-dialkyl-1,3-dioxanes and use of the dioxanes to prepare Iopamidol.
The ketals of 2-amino-1,3-propanediol are advantageously used as synthetic intermediates in the preparation of the compound (S)-N,N'-bis-(2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl) amino]-2,4,6-triido-1,3-benzenedicarboxamide, known with the International Nonproprietary Name of Iopamidol (Merck Index, XI ed., page 799, No. 4943).
Iopamidol was first described by the Swiss Company Savac A.G. in the British patent No. 1,472,050 and is used in diagnostics as a non ionic X-rays contrast medium. The preparation of Iopamidol, as described in said patent, comprises the condensation reaction of L-5-(2-acetoxy-propionylamino)-2,4,6-triido-isophthalic acid dichloride with 2-amino-1,3-propanediol, better known as serinol, in dimethylacetamide and in the presence of a base.
In the same patent, there is described an alternative method comprising the condensation reaction of the above acid dichloride, with a ketal of serinol. The subsequent acid hydrolysis of the formed diketal, carried out by conventional techniques, permits formation of the desired Iopamidol product. 5-Amino-2,2-dialkyl-1,3-dioxanes are among the possible ketals of serinol which can be used in the aforementioned synthesis of Iopamidol.
Several processes for the preparation of 5-amino-2,2-dialkyl-1,3-dioxanes are reported in the literature.
British patent application No. 2,081,256 (Rhone-Poulenc Industries) and U.S. Pat. No. 3,812,186 (Eprova A.G.) describe the preparation of 5-amino-2,2-dialkyl-1,3-dioxanes by catalytic hydrogenation of the corresponding 5-nitro derivatives, prepared, in turn, by direct cyclization of 2-nitro-1,3-propanediol with a suitable ketone, in the presence of boron trifluoride etheate.
U.S. Pat. No. 4,978,793 (W.R. Grace & Co.) describes the preparation of 5-amino-2,2-dialkyl-1,3-dioxanes. The process described involves synthesis of the corresponding 5-nitro-derivatives, through a three step process starting from nitromethane and formaldehyde, and subsequent reduction of the nitro group. The aforesaid processes for the preparation of 5-amino-2,2-dialkyl-1,3-dioxanes as described in the literature have the drawback of using nitro derivatives as intermediates, which are particularly unstable and explosive compounds.
One object of the present invention is a process for the preparation of 5-amino-2,2-dialkyl-1,3-dioxanes of the formula: ##STR3## wherein R and R.sub.1, are the same or different, and represent a straight or branched C.sub.1 -C.sub.3 alkyl group or, together with the carbon atom to which they are bonded, form a C.sub.5 -C.sub.6 cycloaliphatic ring.
A second object of the invention is the formation of 5-amino-2,2-dialkyl-1,3-dioxane of the formula I and the further reaction of the 5-amino-2,2-dialkyl-1,3-dioxane with 1-5-(2-acetoxy-propionylamino)-2,4,6-triido-isophthalic acid dichloride followed by hydrolysis to produce Iopamidol.
The 5-amino-2,2-dialkyl-1,3-dioxanes of formula I are prepared by a process comprising the transformation of a 2,2-dialkyl-1,3-dioxane-5-carboxylic acid ester of formula ##STR4## wherein R.sub.2 represents a straight or branched C.sub.1 -C.sub.3 alkyl group, a phenyl optionally substituted by nitro groups or a benzyl; into the corresponding amide of formula ##STR5## wherein R and R.sub.1, have the above reported meanings and the subsequent rearrangement of the amide to obtain 5-amino-2,2-dialkyl-1,3-dioxanes of formula (I).
The compounds of formula (I) thus obtained can be used as such, for instance as described above and in the aforementioned British patent No. 1,472,050 to produce Iopamidol, or hydrolyzed according to conventional techniques to obtain serinol, which may then be used to produce Iopamidol. Specific examples of the compounds of formula (I) are:
5-amino-2,2-dimethyl-1,3-dioxane PA0 5-amino-2,2-diethyl-1,3-dioxane PA0 5-amino-2,2-di-n.propyl-1,3-dioxane PA0 5-amino-2-ethyl-2-methyl-1,3-dioxane PA0 3-amino-1,5-dioxaspiro[5.5]undecane PA0 3-amino-1,5-dioxaspiro[4.5]decane
Transformation of the ester of formula II into the corresponding amide of formula III may be carried out by treatment with ammonia, preferably in an aqueous solution. The compounds of formula III are then easily isolated by evaporating the solvent.
Rearrangement of the intermediate amides of formula III may be carried out by treatment with a hypohalogenite such as, for instance, sodium hypobromite or sodium hypochlorite, in an aqueous solution.
It is preferred to use sodium hypobromite, which may be prepared in situ from sodium hydroxide and bromine.
The ester compounds of formula II are known or easily prepared according to known methods (H. A. Bates et al., J. Org. Chem., 1986, 51. 2637-2641).
The 5-aminocarbonyl-2,2-dialkyl-1,3-dioxanes of formula III are new and they are a further object of the present invention.
Preparation of the amides, in general, can be carried out according to several standard methods described in the literature (see for a general review March, Advanced organic Chemistry, IV ed., pages 1275-1276). In this connection, without exceeding the scope of the present invention, 5-aminocarbonyl-2,2-dialkyl-1,3-dioxanes of formula III, can be thus prepared according to the aforementioned methods.
A preferred embodiment of the process of the present invention is the following.
A 2,2-dimethyl-1,3-dioxane-5-carboxylic acid ester is treated with an aqueous solution of ammonia for a few hours at room temperature. By evaporating the solvent the crude 5-aminocarbonyl-2,2-dimethyl-1,3-dioxane is obtained in practical quantitative yields and used as such in the subsequent rearrangement reaction.
5-Aminocarbonyl-2,2-dimethyl-1,3-dioxane is added to a basic aqueous solution of sodium hypobromite, prepared in situ from sodium hydroxide and bromine, and heated for a few hours at 80.degree. C. After the evaporation of the water, the residue is collected and purified by treatment with an organic solvent affording 5-amino-2,2-dimethyl-1,3-dioxane in good yields.
5-Amino-2,2-dimethyl-1,3-dioxane is condensed with L-5-(2-acetoxy-propionylamino)-2,4,6-triido-isophthalic acid dichloride to obtain L-5-(2-acetoxy-propionylamino)-2,4,6-triido-isophthalic acid bis-(2,2-dimethyl-1,3-dioxane-5-yl-amide).
The latter can be rendered pure by re-crystallization from isopropanol. The ketal groups may be split by treatment with as little as 0.1N hydrochloric acid whereupon the substance dissolves. The pH of the solution is then adjusted to 11 whereupon the acetoxy group is saponified.
The process objects of the present invention are particularly suitable for an industrial application also because they use starting products which are easily prepared.
Both the intermediates and the starting products are stable and therefore do not present the risk of dangerous and unwanted reactions (explosions) during the accomplishment of the process.
Moreover the process objects of the present invention do not require drastic reaction conditions, such as for instance reduction at high pressures. Another particularly advantageous aspect is that the whole process is carried out in an aqueous environment allowing an easy recovery of the desired products in good yields.
With the aim to better illustrate the present invention, without limiting it, the following examples are now given.